A middle-aged man while watering plants noticed a bruise on his hands. In the next three days, the bruising became extensive, involving both the arms and hands. He decided to visit a physician. His medical history showed that he was not taking anticoagulants or nonsteroidal anti-inflammatory drugs, and reported no other bruise, nosebleeds, blood in urine, bloody stools, and joint or muscle pains. He did not have a history of liver disease, nor did he have any personal or family history of bleeding or clotting disorder.
Local examination showed no other bleeding sites. Systemic examination showed normal kidney and liver function. Laboratory blood investigations showed normal complete blood count, prothrombin time, and INR. However, the activated partial thromboplastin time (aPTT) was elevated, which after further analysis suggested that clotting factor inhibitors were present in the patient’s blood. Further assays revealed factor VIII inhibitors and Acquired hameophilia (AHA) was diagnosed.
What is Acquired Haemophilia?
Acquired hameophilia is a rare autoimmune but life-threatening disorder not present at birth but develops suddenly at some point in life. It is not congenital in nature and occurs due to some immunologic problems (auto-immune disease). Here, the immune system makes antibodies which destroy this clotting factor and prevent blood from clotting.
How is it different from Congenital Haemophilia?
Congenital Haemophilia predominantly affects males and occurs early in life whereas in AHA both sexes get affected equally. It usually occurs when a person is in middle age. The joints mainly get affected in Congenital Haemophilia whereas in AHA bleeding happens mostly in the skin and soft tissues. Bleeding in the muscles, urine, stool, and nose are also seen in the acquired version of Haemophilia.
How rare is it?
Acquired hameophilia is mostly associated with some sort of immunologic disease. It is significantly rarer than the inherited form, affecting around two per million of the population.
How is it diagnosed?
The initial diagnosis depends upon the medical history, physical examination, and imaging studies [blood findings show prolonged activated partial thromboplastin time (aPTT)] and a low factor VIII level for internal bleeding. Confirmatory diagnosis is done with the Bethesda inhibitor assay.
What are the characteristics of AHA inhibitors?
The antibody associated with AHA are usually polyclonal IgG4 antibodies directed towards factor VIII and bind to different domains of antibody. Interference with C-domain prevent attachment of factor VIII to Von Willebrand Factor (VWF) and phospholipids while interference with A-domain block the binding of FVIII to factor X and factor IXa respectively and hinder the formation of the Xa complex which is essential for the final step of the clotting process.
How to manage Acquired Haemophilia?
The management of AHA requires a two-pronged, parallel approach:
– Control the bleeding (Hemostatic Therapy)
– Eradicate the inhibitor
Minor bleeding requires routine hemostatic techniques like the avoidance of invasive procedures and discontinuation of any therapies that can exacerbate bleeding, i.e., antiplatelet or anticoagulant drugs while the cases of major bleeding (seen in 72% patients) require prompt initiation of anti-hemorrhagic treatment.
The first line treatment includes Human FVIII concentrates or Desmopressin where the inhibitor titer is ≤5 Bethesda units (BU) whereas cases with 5 BU require bypassing therapy as the treatment of choice. Two bypassing agents are available for this treatment: plasma-derived activated prothrombin complex concentrate (aPCC) which contains exogenously activated FII, FVII, FIX, and FX, and recombinant activated FVII (rFVIIa). Both achieve hemostasis by generating thrombin (in the absence of FVIII) at the site of bleeding.
Immunosuppression to eradicate an acquired inhibitor should begin immediately upon diagnosis in all patients. It includes,
– Steroids and Cyclophosphamides: Prednisone, Oral Cyclophosphamide, Azathioprine, etc.
– Monoclonal Antibody: Rituximab, Calcineurin Inhibitors (e.g., Cyclosporine, Tacrolimus)
The prognosis depends on the patient’s response to immunosuppression. These three factors have an independent impact on the overall and disease-free survival: related conditions (malignancy vs postpartum), complete remission status, and age at diagnosis.
Two months after the patient finished the course of prednisone, his aPTT time was again prolonged. He was the put-on course of cyclophosphamide and prednisone. Currently he is maintained on 50 mg of cyclophosphamide daily, with a normal activated partial thromboplastin time and no further bleeding.